Preparation of α-aza-amino acid precursors and related compounds by novel methods of reductive one-pot alkylation and direct alkylation

Abstract

Peptiidid koosnevad aminohaptest ja omavad elusorganismis väga tähtsat rolli, reguleerides suurt hulka organismis toimuvatest protsessidest. Kahjuks on aga peptiidide ravimitena kasutamine raskendatud. Suurimaks problemiks on see, et organismis on olemas ensüüme, mis esimese võimaluse korral peptiidi tükkideks lagundavad ja seeläbi nende vajalik aktiivsus kaob. Selle tõttu on arendatud erinevaid peptiidide stabiilsuse tõstmise võtteid. Üheks variandiks on loodusliku kiraalse aminohappe asendamine asa-aminohappega, mille struktuuris on kiraalne C-aatom asendatud lämmastiku aatomiga. Sellist struktuuri looduses ei esine ja ensüümid ei saa sellise peptiidi lagundamisega kergesti hakkama. Kahjuks ei ole aga asa-aminohapped püsivad ja lagunevad iseeneselikult. Selle tõttu on vaja asa-peptiidide sünteesiks asa-aminohapete prekursoreid, mis on hüdrasiini kaitstud derivaadid. Nende ühendite valmistamine on raskendatud lähteainete halva kättesaadavuse, pikkade sünteesiskeemide ning kalleid väärismetalle sisaldavate katalüsaatorte ja keerulise eriaparatuuri vajaduste tõttu. Seepärast ei ole ka kõikide looduslike aminohapetel asa-prekursoreid seni kirjeldatud ning nende saamiseks on vajalik arendada uusi ja mugavamaid sünteesimeetodeid. Käesolev doktoritöö kirjeldab mitut uut asa-aminohappe prekursorite sünteesimeetodit ja samuti on töös valmistatiud seni puudunud asa-metioniini prekursorid.

Peptides consist of amino acid residues and have very important role in living organisms being responsible for regulation of different physiological processes. Unfortunalety, application of peptides as drugs is complicated.The main problem is the presence of different peptide degrading enzymes. As a result of their activity, biologivcally non-active peptide fragments are formed. Due to this problem different strategies for increasing peptide stability were developed. One possibility is the replacement of native chiral amino acid by aza-amino acid where the chiral C-atom is replaced with N-atom. This replacement yields peptidomimetics, which are structurally verly similar to natural peptides. However, as these compounds are not available in nature, the peptide-degrading enzymes are unable to degrade them rapidly. Unfortunately, aza-amino acids are unstable and spontaneously decompose. Due to this problem corresponding protected alkylhydrazines are reguired as aza-amino acid precursors. Preparation of corresponding precursors is often complicated due to poor availability of starting reagents, the preparation proceeds over long synthetic routes, requires expensive precious metal catalysts and special equipment. It is also important to mention that aza-precursors are not described for all the natural amino acids. Due to these obstacles there is a need for a new, more convenient synthetic routes, which will help to complete the list of aza-precursors for replacement of as many as possible amino acids. The present dissertation describes development of several new synthetic methods for preparation of aza-amino acid precursors and synthesis of previously unknown aza-methionine precursors.